2&#39;-acyl-2-aminoxyacetanilide having 2-amino function protected

ABSTRACT

2&#39;&#39;-ACYL-2-AMINOXYACETANILIDE HAVING THE 2-AMINO FUNCTION PROTECTED AND SUBSTITUTED DERIVATIVES THEREOF. THESE COMPOUNDS ARE INTERMEDIATES IN THE PREPARATION OF 4,1,5BENZOXADIAZOCIN-2-ONES (A) WHICH COMPOUNDS ARE CONVERTIBLE INTO 3-HYDROXY-1,4-BENZODIAZEPIN-2-ONES (B). BOTH COMPOUND A AND COMPOUND B ARE ACTIVE AS ANTICONVULSANTS, MUSCLE RELAXANTS AND SEDATIVE AGENTS.

gx nitecl States Patent 1 Patented June 29, 1971 US. Cl. 260-326 14Claims ABSTRACT OF THE DISCLOSURE 2'-acyl-2-aminoxyacetanilide havingthe 2-amino function protected and substituted derivatives thereof.These compounds are intermediates in the preparation of 4,1,5-benzoxadiazocin-Z-ones (A) which compounds are convertible into3-hydroXy-1,4-benzodiazepin-2-ones (B). Both compound A and compound Bare active as anticonvulsants, muscle relaxants and sedative agents.

RELATED APPLICATIONS This application is a division of co-pendingapplication Ser. No. 600,347, filed Dec. 6, 1966, now US. Pat. No.3,420,817, in the names of Arthur Stempel and Leo Henryk Sternbach,which application is in turn a continuationin-part of copendingapplication Ser. No. 522,397, filed Jan. 24, 1966, now abandoned, alsoin the names of Arthur Stempel and Leo Henryk Sternbach. The benefit ofthe dates of these earlier filed applications is hereby claimed.

DETAILED DESCRIPTION The said 2'-acyl-2-aminoxyacetanilide having the 2-amino function protected and its substituted derivates thereof of theFormula IV illustrated hereinafter are intermediates in the preparationof 4,1,5-benzoxadiazocin-2- ones as is noted above. These compounds areconvertible into 3-hydroxy-1,4-benzodiazepin-2-ones with base.

The said 3-hydroXy-benzodiazepines are of the formula wherein A isselected from the group consisting of lower alkyl and C -C cycloalkyl;R, R and R are selected from the group consisting of hydrogen, halogen,nitro, trifluoromethyl and lower alkyl and R and R are each selectedfrom the group consisting of hydrogen and lower alkyl.

A comprehensive survey of the various process aspects of the hereindisclosed invention may be had by reference to the followingdiagrammatical flow sheet wherein the symbols A, R, R R R and R have thesame significance as ascribed thereto hereinabove; X designates ahalogen atom, preferentially, selected from the group consisting ofchlorine, bromine and iodine, R is selected from the group consisting ofhydrogen and lower alkyl and the character Z connotes a readilyremovably nitrogen protecting system. Preferably, R in the formulaeillustrated in the said fiow sheet is hydrogen. In a still morepreferred embodiment, R and R are both hydrogen. In an equally preferredvariation, A is the grouping Still more preferred are those compoundswherein R and R are both hydrogen, A is the grouping and R is halogen,most advantageously, chlorine. In the most preferred embodiment, A isthe grouping R, R and R are all hydrogen and R is halogen,preferentially, chlorine. When A is the grouping and R is other thanhydrogen, R is advantageously joined to the phenyl group in the2-position thereof and is, preferentially, fluorine.

Ilia R NH +HOCCHON R1 4 I XII XI A R4 R3 R4 R3 R R I NCOCHX NCOCHON a+Ho1f1 R1 R1 (11:0 IlI l= A A n iv a? a e R N- R NoooHoNH,

I CHE-Ra l 134- 0 R1 \(lJ=N/ vr v On reference to the flow sheet inwhich the process aspects of the present invention are illustratedgraphically, one important aspect involves reacting ahaloacetamidophenyl derivative, e.g. a haloacetamidobenzophenone of theFormula II above, with a hydroxylamine derivative of the Formula IIIabove which has its nitrogen function protected by a readily removablenitrogen protecting system. By proceeding accordingly, there is obtaineda novel 2-aminoxyacetanilide of the Formula IV above having its terminalnitrogen atom protected by the system Z. The protecting system Z of theso-formed compound is subsequently removed whereby to obtain a novelZ-aminoxyacetanilide of the Formula V above.

Yet another important variation involves reacting an aniline derivativeof the Formula XI above with an aminooxyacetic 'acid derivative whichhas its amino-nitrogen function also protected by the readily removablenitrogen protecting system Z to thereby obtain, in a different mannerthan that described in the preceding paragraph, the novelZ-aminoxyacetanilides of the Formula IV.

Another important process aspect of the invention relates to a procedurefor preparing novel 4,1,5-benzoxadiazocin-Z-ones of the Formula VI abovevia the ring closure of the said novel 2-aminoxyacetanilides of theFormula V above.

Still another important process variation relates to the reaction of anu-oxime of a 2-amino phenyl ketone of the Formula VII above with ahaloacetic acid or an ester thereof to thereby prepare a novel imine(Schifis Base) of the Formula VIII above and ring closing the same tothe corresponding 4,l,S-benzoxadiazocin-Z-one of the Formula VI.

Still another important embodiment of the present invention relates to aprocess for converting the said 4,1,5- benzoxadiazocin-Z-ones of theFormula VI above into a 1,4-benzodiazepin-2-one bearing a hydroxy groupin position-3 of the Formula I above.

As is indicated above, compounds of the Formulas IV, V, VI and VIII arenovel and are useful in view of their capability of being converted intotherapeutically desirable compounds. Thus, such compounds constitute apart of the present invention.

Again, referring to the diagrammatical flow sheet illustratedgraphically hereinabove and considering in greater detail the varioussteps and stages of the processes of the invention disclosed therein,the stage II IV comprises the conversion of a 2-haloacetamido phenylketone of the Formula II above, e.g. a 2-haloacetamidobenzophenone, intoa Z-aminoxyacetanilide of the Formula IV (e.g. a 2'-benzoyl 2aminoxyacetanilide) having the terminal amino function thereof protectedby a suitable protecting system via the reaction of the former with ahydroxylamine derivative of the Formula III above which has the nitrogenfunction thereof protected by the said protecting system Z. Saidprotecting system Z is comprised of a group or groups which are readilyremovable by conventional procedures, well documented in the literature.All that is required of the protecting system Z in order to render itsuitable for the purposes of the present invention is that it be anoperable protecting system for the nitrogen function of a compound ofthe Formula III above, that is, that it protects against the formationof unwanted side products insofar as the present inventron is concerned,which would result if a compound of the Formula III above were to jointo the compound of the Formula II above through the Z-amino nitrogenfunction of the latter. Systems for which the character Z is assignedand which will function efiicaciously for the purposes of the presentinvention are those which consist of the phthaloyl group, a loweralkylidene group, e.g. isopropylidene, a benzal group or onecarbobenzoxy group and one hydrogen group. Representative ofhydroxylamine derivatives bearing a protecting group falling within thescope of the genus encompassed by Formula III above are N hydroxyphthalimide, lower alkylidene oximes, such as acetone oxime,N-carbobenzoxy hydroxylamine, benzaldoxime and the like. It is, ofcourse, to be understood that the compounds expressly named herein whichare encompassed by the genus illustrated in Formula III above are onlyexemplary of the many the artisan would recognize are included withinthe purview of the present invention. Thus, from the above, it should beevident that the character of the system Z as illustrated in thehereinabove formulae is not critical and that for the system Z to beusable for the purposes of the present invention, it need only protectthe nitrogen function of a compound of Formula III above fromparticipating in the above-described first-stage reaction step andcontain leaving groups which are readily removable by well establishedtechniques, whereby to render the terminal nitrogen atom capable ofparticipating in subsequent reaction steps.

Advantageously, the first stage (II IV) is eifected in the presence ofan inert organic solvent such as an ether, e.g. tetrahydrofuran and thelike. To insure good yields of the compounds of the Formula IV above,there is preferentially provided in the reaction zone, a tertiaryorganic base which functions as an acid acceptor to accept thehydrohalic acid formed. Suitable organic bases are tertiary amines suchas tri-lower alkylamines, e.g. triethylamine, dimethylaniline,diethylaniline and the like. While temperature is not a critical aspectof this stage, elevated temperatures are preferred, e.g. at about thereflux temperature of the reaction medium. Thus, the reaction isconveniently effected by heating the reactants together, while agitatingwell, preferably in the presence of a tertiary organic bases as acidacceptor.

The stage IV V, i.e. the stage in which the removal of the protectingsystem is effected, as is noted above, is conducted utilizingconventional procedures well established in the art. For example, if Zin Formula IV above consists of a phthaloyl group as the protectivegroup, the system and its function is removed by treating such compoundswith hydrazine hydrate, whereby to prepare the corresponding compound ofthe Formula V above. If the system Z in a compound of the Formula IVabove consists of a lower alkylidene group, e.g. an isopropylidenegroup, said group being joined to the terminal nitrogen atom of thecompound of the Formula IV above, the conversion of the last-mentionedcompound is effected utilizing a dilute mineral acid, e.g. dilutehydrochloric acid. If Z in the Formula IV above consists of theremovable group, benzal, the conversion of a so-substituted compound ofthe Formula IV above to the corresponding compound of the Formula Vabove can be similarly effected utilizing dilute mineral acids. If thesystem Z consists of carbobenzoxy as the removable group and hydrogen,then removal of the system and its function is effected utilizing ahydrogen bromide-acetic acid mixture. Preferably, the conversion of acompound of the Formula IV above to the corresponding compound of theFormula V above is effected under mild conditions, for example, at roomtemperature.

The stage (V VI) is a particularly novel aspect of the present inventionsince it results in the unexpected ring closure of a compound of theFormula V above to a novel compound of the Formula VI above.Preferentially, this process step is conducted in the presence of anorganic base such as pyridine, picoline, quinoline and the like or asalt thereof or mixtures of the salt and free base. Alternatively, anysuitable inert organic solvent such as a lower alkanol, an ether such astetrahydrofuran, dimethylformamide and the like, can serve as thereaction medium. While an organic base is indicated above as beingpreferentially provided in the reaction medium, it is, of course, to beunderstood that the same is not necessary to a successful performance ofthis process step and the ring c losure can be effected, although withdiminished yields, in aninert organic solvent per se and/or on longstanding at room temperature and/or at elevated temperatures.Temperature and pressure are not critical aspects of this process stepand thus the reaction can be effected at room temperature or above orbelow room temperature and atmospheric pressure. However, elevatedtemperatures, i.e. at about he reflux temperature of the reactionmedium, are preferred.

The last stage of the process illustrated graphically above involvestreating a compound of the Formula VI above with a base to unexpectedlyobtain rearrangement to the desired 3-hydroxy benzodiazepin-Z-ones ofthe Formula I above. Any suitable base which is capable of effecting thedesired end can be suitably employed in this process stage.Representative of such are alkali metal hydroxides, e.g. sodiumhydroxide; alkaline earth metal hydroxides; alkylates, e.g. alkali metalalkylates, such as sodium methoxide, sodium ethoxide and the like.Advantageously, the last stage is conducted in the presence of an inertorganic solvent such as dioxane, tetrahydrofuran, dimethylformamide,lower alkanols such as ethanol and methanol and the like and at roomtemperature and atmospheric pressure, although if the reaction isconducted above or below room temperature, the desired end can also beeffected.

Another stage in the process illustrated diagrammatically above involvesthe step of reacting a compound of the Formula XI with a compound of theFormula XII whereby to obtain a corresponding compound of the FormulaIV. This stage (XI+XII IV) comprises the conversion of the Z-carbonylgroup containing aniline derivatives of the Formula XI, e.g. aZ-amino-benzophenone, a (Z-methyl amino phenyl)lower ketone or a(Z-amino phenyl)C -C cycloalkyl ketone, into the 2-aminoxy acetic acidaniline of the Formula IV above which has the amino function thereofprotected by the protecting system Z. The conversion is effected byreacting the compound of the Formula XI with an aminoxy aceticderivative of the Formula XII which has the nitrogen function thereofprotected by the above-identified protecting system Z. Representative ofaminoxyacetic acid derivatives bearing a protecting group falling withinthe scope of the genus encompassed by Formula XII above arecarbobenzoxyaminoxyacetic acid, phthalimidoxyacetic acid, loweralkylideneaminoxy acetic acid, benzaldaminoxyacetic acid and the like.It is to be understood that the compounds expressly named herein whichare encompassed b y the genus illustrated in Formula XII above are onlyexemplary of the many the artisan would readily recognize are suitablefor the purposes of the present invention and hence, are included withinthe purview thereof.

Advantageously, the conversion of the compound of the Formula XI aboveto the corresponding compound of the Formula IV above is effected in thepresence of an inert organic solvent which may be a chlorinatedhydrocarbon such as methylene chloride, ethers such as tetrahydrofuran,an aromatic hydrocarbon such as benzene and toluene and the like. In apreferred aspect, when converting the compounds of the Formula XI aboveto the corresponding compounds of the Formula IV above, a condensingagent is present. Among the many conldensing agents suitable for thepurposes of the present invention there may be includedN,N-dicyclohexylcarbodiimide, thionyl chloride, polyphosphoric acid andthe like. Most preferred is N,N'-dicyclohexylcarbodiimide. Temperatureand pressure are not critical aspects of this process variation.Accordingly, the process can be carried out at room temperature and atelevated temperatures.

However, in a preferential aspect, the process is carried out below roomtemperature, most preferably, from a temperature of 0 C. to about 15 C.

Another stage in the process illustrated diagrammatically above involvesthe route from VII VIII VI. When converting the compound of the FormulaVII above (a compound which contains an oxime group, syn with respect tothe amino substituted phenyl group), to the corresponding compound ofthe Formula VIII above, with a haloacetic acid or an ester thereof,there is present as the reaction medium, an inert organic solvent whichmay be a lower alkanol such as methanol, ethanol and the like, an ethersuch as dioxane, tetrahydrofuran, N,N- dimethylformamide, dimethylsulfoxide and the like. Preferably, the reaction medium in which theconversion is effected is made basic by the addition thereto of a basicmaterial, preferably, a material which is strongly basic, vsuch as alower alkali metal hydroxide, e.g. sodium hydroxide, a lower alkalimetal al'koxide, e.g. sodium methoxide and the like. While temperatureand pressure are not critical aspects of this process variation, it ispreferred to operate at elevated temperatures, most preferably, at aboutthe reflux temperature of the reaction medium.

The conversion of the compounds of the Formula VIII above to thecorresponding compounds of the Formula VI above is suitably effected inthe presence of a cyclization agent and an inert organic solvent mediumsuch as tetrahydrofuran and the like. Any suitable cyclization agentwhich is capable of achieving the desired end can be efficaciouslyemployed in this process variation. Illustrative of such areN,N'-dicyclohexyl-carbodiimide, p-toluene sulphonic acid, thionylchloride, polyphosphoric acid and the like. In a preferred embodiment,in this ring closing step when R is H, the cyclization agent utilized isN,N- dicyclohexylcarbodiimide. -In this process step, temperature andpressure are not critical. However, when R is hydrogen, it is preferredto operate below room temperature, preferentially in a range from about0 C. to about 25 C. When R is lower alkyl elevated temperatures arepreferred, e.g. at about the reflux temperature of the reaction medium.

Compounds of Formula VI above are useful not only as intermediates inthe preparation of compounds of known therapeutic value but areadditionally useful as anticonvulsant', muscle relaxant and sedativeagents. Particularly useful for such purposes are compounds of theFormula VI above wherein R is lower alkyl, e.g. methyl and A is thegrouping wherein R is as above. The compounds of Formula VI above can beadministered, parenterally or enterally, with the dosage regimenadjusted to fit the exigencies of a particular pharmacologicalsituation. They can be compounded in conventional pharmaceutical dosageforms to provide capsules, tablets, elixirs, suppositories, suspensions,emulsions and the like.

Compounds of Formula VI above wherein R is lower alkyl can besynthesized from compounds of Formula VI above wherein R is hydrogen byalkylating such compounds. The alkylation can be efficaciously effectedby treating compounds corresponding to Formula VI above wherein R ishydrogen with, for example, an alkali metal hydride, e.g. sodium hydrideor an alkali metal alcoholate such as sodium methoxide in the presenceof an inert organic solvent such as toluene, dimethylformamide and thelike to thereby form the sodio derivative of such compounds and thenreacting the sodio derivative with an alkylating agent, e.g. a di-loweralkyl sulfate or a lower alkyl halide. Suitable dialkyl sulfates may berepresented by dimethyl sulfate. Similarly, suitable alkyl halides maybe represented by methyl iodide.

The term lower alkyl as utilized hereinabove is intended to representstraight or branched chain hydrocarbon groups such as methyl, ethyl,propyl, isobutyl and the like. The term halogen as employed hereindesignates all four forms thereof, chlorine, fluorine, bromine andiodine, unless otherwise specified. The expression C -C cycloalkylconnotes a cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl andcycloheptyl group.

The foregoing is a description of new and valuable processes for thepreparation of pharmaceutically useful3-hydroxy-1,4-benzodiazepin-2-ones and novel intermediates useful intheir preparation. It will be readily apparent to one skilled in the artthat variations of these procedures are possible.

The following examples are illustrative but not limitative of theprocess for preparing the aforesaid 3-hydroxybenzodiazepin-Z-ones, thenovel intermediates useful in the preparation thereof and novelbenzoxadiazocines which are additionally useful for pharmaceuticalpurposes. All temperatures are stated in degrees centigrade.

Example 1 A mixture of 10 g. (28 mmoles) of 2-benzoyl-2-bromo-4'-chloroacetanilide and 4.6 g. (28 mmoles) of N-hydroxyphthalimide in60 ml. of tetrahydrofuran containing 8.6 ml. of triethylamine wasstirred and heated to reflux for a period of 75 minutes. The resultantmixture was then filtered. On addition of hexane to the filtrate,crystallization occurred. Filtration separated 2-benzoyl-4'-chloro-2-phthalimidoxyacetanilide, melting at 179-181.5. Recrystallization fromethyl acetate gave the product melting at 183-1 84".

Example 2 A mixture of 21.6 g. (59 mmoles) of 2-benzoyl-2-bromo-4-nitroacetanilide and 9.6 g. (59 mmoles) of N- hydroxyphthalimidein 130 ml. of tetrahydrofuran and 18.1 ml. of triethylamine was stirredand heated to reflux for 75 minutes. It was then filtered. On additionof hexane to the tetrahydrofuran filtrate, 2'-benzoyl-4-nitro-2-phthalimidoxyacetanilide melting at 183.5185 crystallized.Recrystallization from ethyl acetate gave cream colored needles meltingat 203204.

Example 3 A mixture of 24.2 g. (63 mmoles) of 2'-benzoyl-2- bromo4'-trifiuoromethylacetanilide and 10.3 g. (63 mmoles) ofN-hydroxyphthalimide in 135 ml. of tetrahydrofuran and 19.3 ml. oftriethylamine was stirred and heated to reflux for 75 minutes. Theresultant mixture was then filtered. Upon addition of hexane to thefiltrate, crystallization occurred. Filtration separated crude 2'-benzoyl 4' trifiuoromethyl-Z-phthalimidoxyacetanilide melting at184-189. Recrystallization from ethylacetate gave the product melting at191-193".

Example 4 Using the procedure described in Example 3, 2'-benzoyl-2-phthalimidoxyacetanilide melting at 174-176 was prepared by reacting2-benzoyl-2-bromoacetanilide with N- hydroxyphthalimide.

Example 5 To a solution of 6.8 g. (16 mmoles) of 2-benzoyl-4'-chloro-Z-phthalimidoxyacetanilide in a mixture of 80 ml. of chloroformand 80 ml. of ethanol, 1.8 g. (37 mmoles) of hydrazine hydrate and 1.8ml. of water were added. After standing for 18 hours at roomtemperature, the mixture was filtered. The filtrate was concentrated toa small volume under reduced pressure and the residue was thenpartitioned between dilute ammonia water and ether. The ether layer wasseparated and extracted with a 5% solution of hydrochloric acid. Theacidic extracts were combined, made slightly basic with dilute sodiumhydroxide and extracted with ether. The organic layer was dried oversodium sulfate and concentrated to dryness. The residue As in Example 5,2-aminoxy-2'-benzoyl-4-nitroacetanilide was prepared from2'-benzoyl-4'-nitro-2-phthalimidoxyacetanilide. It melted at 141l43after crystallization from a mixture of benzene and hexane.

Example 7 As in Example 5,2-aminoxy-2'-benzoyl-4'-trifluoromethylacetanilide was prepared from2'-benzoyl-4-trifluoromethyl-Z-phthalimidoxyacetanilide. It crystallizedfrom hexane as colorless plates melting at 7981.

Example 8 As in Example 5, Z-aminoxy-2'-'benzoylacetanilide was preparedfrom 2-benzoyl-2-phthalimidoxyacetanilide.

Example 9 A solution of 5 g. (16 mmoles) of2-aminoxy-2-benzoyl-4'-chloroacetanilide in ml. of pyridine wascarefully added over a period of 1 hour to a stirred, refluxing solutionof 5 g. of pyridine hydrochloride in 600 ml. of pyridine. Uponcompletion, the refluxing was continued for an additional 6 hours.Solvent was then distilled off under reduced pressure and the residuewas partitioned between methylene chloride and water. The organic layerwas washed successively with dilute hydrochloric acid, 5% sodiumbicarbonate solution and water. After drying over sodium sulfate, thesolvent was removed by distillation and the residue crystallized fromethyl acetate. The filtrate was distilled to remove ethyl acetate andthe residue was crystallized from benzene to give8-chloro-l,3-dihydro-6- phenyl-2H-4,1,S-benzoxadiazocin-Z-one melting at197- 198.5 Further crystallization did not alter the melting point.

Example 10 As in Example 9,1,3-dihydro-6-phenyl-2H-4,1,5-benzoxadiazocin-Z-one was prepared fromthe 2-aminoxy-2' benzoylacetanilide synthesized in Example 8 and wasfound to have a melting point of 236238 after crystallization frombenzene.

Example 11 As in Example 9, 1,3-dihydro-8-nitro-6-phenyl-2H-4,1,S-benzoxadiazocin-Z-one was prepared from 2aminoxy-2'-benzoyl-4'-nitroacetanilide. The so-prepared product had a meltingpoint of 253255 after crystallization from methylene chloride andhexane.

Example 12 As in Example 9, 1,3-dihydro-8-trifiuor0methyl-6-phenyl-2H-4,1,5-benzoxadiazocin-2-one was prepared from2-aminoxy-2'-benzoyl 4 trifluoromethyl acetanilide. The so-preparedproduct had a melting point of 212-214 after crystallization frommethylene chloride and hexane.

Example 13 A solution of 1 g. (3.5 mmoles) of8-chloro-1,3-dihydro-6-phenyl-2H-4,l,S-benzoxadiazocin-Z-one in 100 ml.of dioxane containing 3.5 ml. of 2 N sodium hydroxide (7 mmoles) wasstirred for 20 hours. A solid formed after about 3 hours of stirring.The solid was separated by filtration and gave the sodium salt of7-chloro-1,3-dihydro- 3 hydroxy-S-phenyl-ZH-l,4-benzodiazepin-2-onemelting at 205 A solution of this product in 100 ml. of ethanol and 45ml. of water (pH 12.2) was acidified to pH 1.7 by the addition of 3 Nhydrochloric acid. On concentration of the acidic solution under reducedpressure, 7-chloro-l,3-dihydro 3 hydroxy-5-phenyl-2H-l,4-benzodiazepin-Z-one crystallized.

9 Example 14 To a solution of 1.0 g. (3.5 mmoles) of 8-chloro-l,3-dihydro-6-phenyl-2H-4,1,S-benzoxadiazocin-Z-one in 50 ml. of methanol,there was added 2.5 ml. of 2.79 N sodium methoxide in methanol (7mmoles). The resultant reaction medium was stirred for 195 min. Thesolid that separated was removed by filtration to give the sodium saltof 7-chloro-1,3-dihydro 3 hydroxy--phenyl-2H-1,4- benzodiazepin-Z-one,M.P. 196-210 dec. The last-mentioned salt was dissolved in 70 ml. of 50%aqueous ethanol and acidified to pH 2 with 3 N hydrochloric acid.7-chloro 1,3 dihydro 3 hydroxy-5-phenyl-2H-1,4- benzodiazepin-Z-onecrystallized, melting point 197-200". More product could be obtained byacidification of the methanol filtrate obtained above.

Example To a solution of 2.0 g. (7 mmoles) of8-chloro-1,3-dihydro-6-phenyl-2H-4,1,S-benzoxadiazocin-Z-one in 25 ml.of dimethylformamide, 0.5 g. (11 mmoles) of sodium hydride (60% inmineral oil) was added. After stirring for 15 minutes at roomtemperature, 1 ml. (2.27 g., 16 mmoles) of methyl iodide was added andthe stirring was continued for 45 minutes. On addition of ice, a whitesolid separated. Filtration separated crude 8-chloro-1,3-dihydro-1-methyl-6-phenyl 2H-4,1,5-benzoxadiazocin-2- one melting at78-82. Recrystallization from hexane gave the pure product melting at130.5-131.5.

Example 16 A solution of 12.0 g. (52 mmoles) of2-amino-5-chlorobenzophenone and 11.7 g. (52 mmoles) ofcarbobenzoxyaminoxyacetic acid in 500 ml. of methylene chloride wascooled to 0 in an ice bath and a solution of 11.6 g. (0.57 mmole) ofdicyclohexylcarbodiimide in 125 ml. of methylene chloride was addeddropwise over a period of 1 hr. After 15 hrs. at room temperature, thereaction medium was filtered. Acetic acid (3 ml.) was added to thefiltrate, solvent was distilled off and the residue stirred withbenzene. The mixture was then again filtered. Solvent was distilled offfrom the last-mentioned filtrate under reduced pressure and the residue,dissolved in methylene chloride, was passed through a column ofFlorisil. Then, methylene chloride was passed through the column.Thereafter, elution with ethyl acetate separated a material.Crystallization of this material from a mixture of benzene and hexanegave 2-benzoyl-2-carbobenzoxyaminoxy-4-chloroacetanilide, melting point113-114".

Example 17 A solution of 7.25 g. of2-benzoyl-2-carbobenzoxyaminoxy-4-chloroacetani1ide in 75 ml. ofhydrobromic acid in acetic acid was stirred for 30 min. at roomtemperature. On addition of 750 ml. of anhydrous ether, a gummy solidformed. After decantation of the supernatant, the gummy residue waspartitioned between ether and 5% sodium bicarbonate. The ether layer wasdried over sodium sulfate and concentrated to dryness. Crystallizationof the residue from a mixture of benzene and hexane gave 2-aminoxy-Z-benzoyl-4-chloroacetanilide (M.P. 85-86).

Example 18 To a refluxing stirred solution of 12.5 g. of pyridinehydrochloride in 1250 ml. of pyridine, a solution of 12.5 g. of2-aminoxy-2'-benzoyl-4-chloracetanilide in 500 ml. of pyridine was addedslowly during 90 min. Refluxing was continued for 5 hours, then pyridinewas removed by distillation under reduced pressure and the residuepartitioned between methylene chloride and-water. The organic layer wasseparated and Washed with dilute hydrochloric acid, dilute sodiumbicarbonate, and dried over sodium sulfate. Solvent was distilled offunder reduced pressure and the residue crystallized from ethyl acetate.The resultant medium was then filtered. The filtrate was concentrated todryness and the residue crystallized from benzene to give8-chloro-1,3-dihydro-6-phenyl-2H-4,1-5-benzoxadiazocin-Z-one, M.P.193-197". Further crystallization from benzene gave heavy colorlessprisms of the product melting at 198-199.

Example 19 To a suspension of g. (0.4 mole) of 2-amino-5-chlorobenzophenone syn-oxime in 1500 ml. of ethanol, 43.2 g. (0.8 mole)of sodium methoxide was added followed by 56 g. 0.4 mole) of bromoaceticacid. The mixture was stirred and heated to reflux for 2 hrs. Solventwas then removed by distillation under reduced pressure. The residue waspartitioned between methylene chloride and water. The organic layer wasseparated and the aqueous layer made more basic by addition of 10%sodium hydroxide. The aqueous layer was again extracted with methylenechloride and filtered through Hy-Flo to remove a small amount ofinsoluble material. On standing, the sodium salt ofN-(2-amino-S-chlorodiphenylmethylene) aminoxyacetic acid (syn-isomer)crystallized. It was separated by filtration, dissolved in 2 l. of waterand upon acidification with 3 N hydrochloric acid, the free acidcrystallized. After recrystallization from aqueous ethanol, N- (Z-amino.5 chlorodiphenylmethylene)aminoxyacetic acid (syn-isomer) melting at164-6 was obtained.

Example 20 A solution of 25.0 g. (82 millimoles) of N-(2-amino-5-chlorodiphenylmethylene)aminoxyacetic acid syn-isomer in 1 l. oftetrahydrofuran was cooled to 5 and a solution of 15 g. (73 millimoles)of N,N-dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran was addedslowly. The mixture was stirred for 15 hrs. at room temperature andfiltered. To the filtrate, 2 ml. of acetic acid were added followed byabout 200 ml. of water. Distillation under reduced pressure removedtetrahydrofuran. The residue was dissolved in methylene chloride andwashed successively with water, 5% sodium bicarbonate, and saturatedsalt solution. After drying the organic layer over sodium sulfate, thesolvent was removed by distillation. The residue was dissolved in hotbenzene and filtered to remove a small amount of insoluble material. Onstanding, 8-chloro-1,3-dihydro-6-phenyl 2H-4, l ,S-benzoxadiazocin-Z-one(M.P. 198-203") crystallized. From the mother liquor, after addition ofhexane, an impure fraction crystallized (M.P. 184-192").

Example 21 To a solution of 13.5 g. (0.1 mole) of o-aminoacetophenone in200 ml. of ether, 100 ml. of water was added. While stirring, 20.2 g.(8.9 ml., 0.1 mole) of bromoacetyl bromide dissolved in 50 ml. of etherwas added slowly. At the same time, dilute sodium hydroxide was added tokeep the mixture slightly alkaline. The ether layer was separated,washed with water and dried over sodium sulfate. Solvent was thenremoved by distillation. The residue crystallized from a mixture ofchloroform and hexane to give 2'-acetyl-2-bromoactanilide melting at64-66".

Example 22 A mixture of 25 g. (98 millimoles) of 2'-acetyl-2-bromoacetanilide and 16 g. (98 millimoles) of N-hydroxyphthalimide in250 ml. of tetrahydrofuran containing 30 ml. of triethylamine wasstirred and heated to reflux for 1% hr. The solid that formed wasseparated by filtration and stirred with water. The water insolublematerial melted at 183-185. Recrystallization of the latter from amixture of chloroform and hexane gave pure 2-acetyl-2-phthalimidoacetanilide melting at 185-186". On addition of water to thetetrahydrofuran filtrate obtained above and removal of tetrahydrofuranby distillation under reduced pressure, an additional amount of crude2-acetyl- 2-phthalimidoacetanilide, M.P. 177-181 was obtained.Recrystallization of the latter from a mixture of chloroform and hexanegave more of the pure product.

1 1 Example 23 A solution of 25 g. (74 millimoles) of 2-acetyl-2-phthalimidoxyacetanilide in a mixture of 400 ml. of alcohol and 400 ml.of chloroform containing 8.5 g. of hydrazine hydrate and 8.5 ml. ofwater was kept at room temperature for 16 hrs. The solid that formed wasseparated by filtration. The filtrate was concentrated under reducedpressure while adding water. The crystalline product,2'-acetyl-2-aminoxyacetanilide, M.P. 103l06, was separated byfiltration. Recrystallization from a mixture of methylene chloride andhexane gave a pure product melting at 105-106.

Example 24 A solution of g. (24 millimoles) of 2'-acetyl-2-aminoxyacetanilide in 200 ml. of pyridine containing 5 g. of pyridinehydrochloride was stirred and heated to reflux for 5 hrs. Pyridine wasthen removed by distillation under reduced pressure. The residue waspartitioned between methylene chloride and water. The organic layer waswashed successively with dilute hydrochloric acid, dilute sodiumbicarbonate and water, then dried over sodium sulfate. After removal ofthe solvent by distillation, the residue was dissolved in hot ethylacetate and filtered. The filtrate was then concentrated to a smallvolume. Crystallization of1,3-dihydro-6-methyl-2H-4,1,5-benzoxadiazocin-Z-one, M.P. 214216occurred. After recrystallization of this product from benzene, it wasfound to melt at 216-217.

Example 25 To a solution of 24.7 g. (0.1 mole) of 2-arnino-5-chlorobenzophenone syn-oxime in 500 ml. of ethanol and 36 ml. of 2.79 Nsodium methoxide in methanol, 16.7 g. (0.1 mole) of ethyl bromoacetatewas added. The mixture was stirred and heated to reflux for 2 hrs., thenconcentrated to a small volume under reduced pressure. A methylenechloride solution of the residue was Washed with water, dried oversodium sulfate and concentrated to dryness under reduced pressure. Theresidue was dissolved in benzene and passed through a column of alumina.The benzene eluate was concentrated to dryness and crystallized fromcyclohexane to give crude N-(2- amino 5chlorodiphenylmethylene)aminoxyacetic acid ethyl ester, syn-isomermelting at 6772. Recrystallization from hexane gave colorless needles ofpure product melting at 8284.

Example 26 A solution of 5 g. mmoles) of :N-(2-arnino-5-chlorodiphenylmethylene)aminoxyacetic acid ethyl ester, syn-isomer and2.9 g. (15 mmoles) of p-toluene sulfonic acid monohydrate in 250 ml. ofxylene was stirred and heated to reflux for hrs. Xylene was then removedby distillation under reduced pressure and the residue was partitionedbetween methylene chloride and water. After drying over sodium sulfate,the organic layer was concentrated to dryness. The residue wastriturated with warm benzene, filtered to remove insoluble material andagain concentrated to dryness. The residue was then triturated withethyl acetate to remove more insoluble material. The residue obtainedafter evaporation of ethyl acetate was dissolved in methylene chlorideand passed through a column of Florisil. Elution with ether gave8-chloro-1,3- dihydro 6-phenyl-2H-4,1,S-benzoxadiazocin-Z-one whichmelted at 198200 after recrystallization from benzene.

Example 27 A solution of 28 mmoles of 2'-benzoyl-2-bromo-4'-chloro-propionanilide syn-oxime and 28 mmoles of N- hydroxyphthalimideand 8.6 ml. of triethylamine in 60 ml. of tetrahydrofuran was stirredand heated to reflux for 75 min. After cooling, filtration separatedtriethyl- 12 amine hydrobromide. On addition of hexane to the filtrate,crystallization occurred and the product was separated by filtrationyielding 2-benzoyl-4'-chloro-2-(phthalimidooxy)-N-propionanilide, M.P.164l66.

Example 28 A solution of 0.2 mole of 2 benzoyl 4' chloro-2-(phthalimidooxy)propionanilide in a mixture of 900- ml. of chloroformand 900 ml. of ethanol containing 21 g. of hydrazine hydrate and 21 ml.of water was kept for 16 hrs. at room temperature. The gelatinousprecipitate of phthalhydrazide that formed was separated by filtration.The filtrate was concentrated under reduced pressure, after addition ofwater to remove chloroform and ethanol. The solid that separated wasremoved by filtration to yield 2-aminoxy-2-benzoyl-4chloropropionanilide. After recrystallization from ethyl acetate, theproduct was found to have a melting point of 104106.

Example 29 As in Example 9, 8-chloro-1,3-dihydro- 3 -methyl-6-phenyl-2H-4,1,5-benzoxadiazocin 2 one was prepared from2-aminoxy-2'-benzoyl-4'-chloropropionanilide. The so-prepared producthad a melting point of 170172 after crystallization from methylenechloride and hexane.

Example 30 A parenteral formulation containing the followingingredients:

Per cc. 8-chloro-1,3-dihydro-6phenyl-2H-4,1,5 benzoxa- Water forinjection q.s., 1.0 cc.

were prepared (for 10,000 cc.) as follows:

5 gm. of 8-chloro-1,3-dihydro-6-phenyl-2H-4,1,5-benzoxadiazocin-Z-onewere dissolved in cc. of benzyl alcohol; 4,000 cc. of propylene glycoland 1,000 cc. of ethanol were added. 12 gm. of benzoic acid weredissolved in the above. 488 gm. of sodium benzoate dissolved in 3,000cc. of water for injection were added. The solution was brought up tofinal volume of 10,000 cc. with water for injection. The solution wasfiltered thru an 02 Selas candle, filled into suitable size ampuls,gassed with N and sealed. It was then autoclaved at 10 p.s.i. for 30minutes.

Example 31 A capsule dosage formulation containing the followingingredients were prepared as follows:

Per capsule, mg. 8-chloro-1,3-dihydro-6-phenyl-2H-4,1,5benzoxadiazocin-Z-one 10 Lactose, U.S.P. Corn Starch, U.S.P. 30 Talc,U.S.P. 5

Total weight 210 The8-chloro-1,3-dihydro-6-phenyl-2H-4,1,5-benxozadiazocin-Z-one, thelactose and the corn starch were mixed in a suitable mixer. Theso-formed mixture Was further blended by passing it through aFitzpatrick Comminuting Machine with a #1A screen with knives forward.The blended powder was returned to the mixer, the talc was added and theresultant mixture was blended thoroughly. The mixture was filled in #4hard shell gelatin capsules on a Parke Davis capsulating machine.

13 Example 32 A tablet dosage formulation containing the followingingredients:

Per tablet, mg. 8-chloro-1,3-dihydro-6-phenyl 2H4,1,5-benzoxadiazocin-Z-one 5.00 Dicalcium phosphate dihydrate, unmilled195.00 Corn starch 24.00 Magnesium stearate 1.00

Total weight 225.00

wherein A is selected from the group consisting of lower alkyl and R, Rand R are each selected from the group consisting of hydrogen, halogen,nitro, trifluoromethyl and lower alkyl; R and R are each selected fromthe grou consisting of hydrogen and lower alkyl; and Z is selected froma nitrogen protecting system consisting of phthaloyl and onecarbobenzoxy group and one hydrogen group.

2. A compound as in claim 1 wherein R and R are both hydrogen and A isthe grouping wherein R is selected from the group consisting of hydrogenand halogen.

3. A compound as in claim 2 wherein R is halogen. 4. A compound as inclaim 2 wherein R is nitro. 5. A compound of the formula Rs I N-COCHONR1 -?=O I wherein A is selected from the group consisting of lower alkyland R, R and R are each selected from the group consisting of hydrogen,halogen, nitro, trifluoromethyl and lower 14 alkyl; and R and R are eachselected from the group consisting of hydrogen and lower alkyl.

6. A compound as in claim 5 wherein R and R are both hydrogen and A isthe grouping wherein R is selected from the group consisting of hydrogenand chlorine.

7. A compound as in claim 6 wherein R and R are hydrogen and R is halo,i.e., a compound of the formula2-benzoyl-4-halo-2-phthalimidoxyacetanilide.

8. A compound as in claim 7 wherein the halo compound is chlorine, i.e.,a compound of the formula 2-benzoyl-4-chloro-2-phthalimidoxyacetanilide.

9. A compound as in claim 6 wherein R is hydrogen and R is nitro, i.e.,a compound of the formula 2'-Rbenzoyl-4'-nitro-2-phthalimidoxyacetanilide wherein R is selected fromthe group consisting of hydrogen and halogen.

10. A compound as in claim 6 wherein R and R are both hydrogen, i.e., acompound of the formula 2'-R benzoyl-2-phthalimidoxyacetanilide whereinR is selected from the group consisting of hydrogen and halogen.

11. A compound of the formula R4 3 H -1 I 0 0 N R! C O Carbobenzoxywherein A is selected from the group consisting of lower alkyl and R, Rand R are each selected from the group consisting of hydrogen, halogen,nitro, trifluoromethyl and lower alkyl; and R and R are each selectedfrom the group consisting of hydrogen and lower alkyl.

12. A compound as in claim 11 wherein R and R are both hydrogne and A isthe grouping wherein R is selected from the group consisting of hydrogenand halogen.

13. A compound as in claim 12 wherein R is halogen and R is hydrogen,i.e., a compound of the formula 2'- R -benzoyl-Z-carbobenzoxyarninoxy 4halo-acetanilide wherein R is selected from the group consisting ofhydrogen and halogen.

14. A compound as in claim 13 wherein R is hydrogen and R is the halogengroup chlorine, i.e., a compound of the formula2-benzoyl-2-carbobenzoxy-aminoxy-4- chloroacetanilide.

References Cited UNITED STATES PATENTS 3,141,890 7/1964 Reeder et al260-326 ALEX MAZEL, Primary Examiner I. A. NARCAVAGE, Assistant ExaminerUS. Cl. X.R.

